Bayesian optimization to estimate hyperfine couplings from 19F ENDOR spectra

ENDOR spectroscopy is a fundamental method to detect nuclear spins in the vicinity of paramagnetic centers and their mutual hyperfine interaction. Recently, site-selective introduction of 19F as nuclear labels has been proposed as a tool for ENDOR-based distance determination in biomolecules, complementing pulsed dipolar spectroscopy in the range of angstrom to nanometer. Nevertheless, one main challenge of ENDOR still consists of its spectral analysis, which is aggravated by a large parameter space and broad resonances from hyperfine interactions. Additionally, at high EPR frequencies and fields (⩾94 GHz/3.4 Tesla), chemical shift anisotropy might contribute to broadening and asymmetry in the spectra. Here, we use two nitroxide-fluorine model systems to examine a statistical approach to finding the best parameter fit to experimental 263 GHz 19F ENDOR spectra. We propose Bayesian optimization for a rapid, global parameter search with little prior knowledge, followed by a refinement by more standard gradient-based fitting procedures. Indeed, the latter suffer from finding local rather than global minima of a suitably defined loss function. Using a new and accelerated simulation procedure, results for the semi-rigid nitroxide-fluorine two and three spin systems lead to physically reasonable solutions, if minima of similar loss can be distinguished by DFT predictions. The approach also delivers the stochastic error of the obtained parameter estimates. Future developments and perspectives are discussed

The beta-Secretase Substrate Seizure 6-Like Protein (SEZ6L) Controls Motor Functions in Mice

The membrane protein seizure 6–like (SEZ6L) is a neuronal substrate of the Alzheimer’s disease protease BACE1, and little is known about its physiological function in the nervous system. Here, we show that SEZ6L constitutive knockout mice display motor phenotypes in adulthood, including changes in gait and decreased motor coordination. Additionally, SEZ6L knockout mice displayed increased anxiety-like behaviour, although spatial learning and memory in the Morris water maze were normal. Analysis of the gross anatomy and proteome of the adult SEZ6L knockout cerebellum did not reveal any major differences compared to wild type, indicating that lack of SEZ6L in other regions of the nervous system may contribute to the phenotypes observed. In summary, our study establishes physiological functions for SEZ6L in regulating motor coordination and curbing anxiety-related behaviour, indicating that aberrant SEZ6L function in the human nervous system may contribute to movement disorders and neuropsychiatric diseases

Super-resolving phase measurements with a multi-photon entangled state

Using a linear optical elements and post-selection, we construct an entangled polarization state of three photons in the same spatial mode. This state is analogous to a ``photon-number path entangled state'' and can be used for super-resolving interferometry. Measuring a birefringent phase shift, we demonstrate two- and three-fold improvements in phase resolution.Comment: 4 pages, 3 figure

Enhanced activity of an ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F) against platelet agglutination in vitro and in a murine model of acute ischemic stroke.

Essentials ADAMTS13 requires a substrate-induced conformational change to attain full activity in vitro. The efficacy of wild type ADAMTS13 in models of thrombosis/stroke may be enhanced by pre-activation. A pre-activated ADAMTS13 variant exhibits enhanced proteolysis of platelet agglutinates. This ADAMTS13 variant is protective in a murine model of stroke at a lower dose than WT ADAMTS13. SUMMARY: Background ADAMTS-13 circulates in a closed conformation, only achieving full proteolytic activity against von Willebrand factor (VWF) following a substrate-induced conformational change. A gain-of-function (GoF) ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F) is conformationally preactivated. Objectives To establish how the hyperactivity of GoF ADAMTS-13 is manifested in experimental models mimicking the occlusive arterial thrombi present in acute ischemic stroke. Methods The ability of GoF ADAMTS-13 to dissolve VWF-platelet agglutinates was examined with an assay of ristocetin-induced platelet agglutination and in parallel-flow models of arterial thrombosis. A murine model of focal ischemia was used to assess the thrombolytic potential of GoF ADAMTS-13. Results Wild-type (WT) ADAMTS-13 required conformational activation to attain full activity against VWF-mediated platelet capture under flow. In this assay, GoF ADAMTS-13 had an EC50 value more than five-fold lower than that of WT ADAMTS-13 (0.73 ± 0.21 nm and 3.81 ± 0.97 nm, respectively). The proteolytic activity of GoF ADAMTS-13 against preformed platelet agglutinates under flow was enhanced more than four-fold as compared with WT ADAMTS-13 (EC50 values of 2.5 ± 1.1 nm and 10.2 ± 5.6 nm, respectively). In a murine stroke model, GoF ADAMTS-13 restored cerebral blood flow at a lower dose than WT ADAMTS-13, and partially retained the ability to recanalize vessels when administration was delayed by 1 h. Conclusions The limited proteolytic activity of WT ADAMTS-13 in in vitro models of arterial thrombosis suggests an in vivo requirement for conformational activation. The enhanced activity of the GoF ADAMTS-13 variant translates to a more pronounced protective effect in experimental stroke

Automatically extracting functionally equivalent proteins from SwissProt

In summary, FOSTA provides an automated analysis of annotations in UniProtKB/Swiss-Prot to enable groups of proteins already annotated as functionally equivalent, to be extracted. Our results demonstrate that the vast majority of UniProtKB/Swiss-Prot functional annotations are of high quality, and that FOSTA can interpret annotations successfully. Where FOSTA is not successful, we are able to highlight inconsistencies in UniProtKB/Swiss-Prot annotation. Most of these would have presented equal difficulties for manual interpretation of annotations. We discuss limitations and possible future extensions to FOSTA, and recommend changes to the UniProtKB/Swiss-Prot format, which would facilitate text-mining of UniProtKB/Swiss-Prot

Analysis of factors influencing the ultrasonic fetal weight estimation

Objective: The aim of our study was the evaluation of sonographic fetal weight estimation taking into consideration 9 of the most important factors of influence on the precision of the estimation. Methods: We analyzed 820 singleton pregnancies from 22 to 42 weeks of gestational age. We evaluated 9 different factors that potentially influence the precision of sonographic weight estimation ( time interval between estimation and delivery, experts vs. less experienced investigator, fetal gender, gestational age, fetal weight, maternal BMI, amniotic fluid index, presentation of the fetus, location of the placenta). Finally, we compared the results of the fetal weight estimation of the fetuses with poor scanning conditions to those presenting good scanning conditions. Results: Of the 9 evaluated factors that may influence accuracy of fetal weight estimation, only a short interval between sonographic weight estimation and delivery (0-7 vs. 8-14 days) had a statistically significant impact. Conclusion: Of all known factors of influence, only a time interval of more than 7 days between estimation and delivery had a negative impact on the estimation

Sensory Electrical Stimulation Improves Foot Placement during Targeted Stepping Post-Stroke

Proper foot placement is vital for maintaining balance during walking, requiring the integration of multiple sensory signals with motor commands. Disruption of brain structures post-stroke likely alters the processing of sensory information by motor centers, interfering with precision control of foot placement and walking function for stroke survivors. In this study, we examined whether somatosensory stimulation, which improves functional movements of the paretic hand, could be used to improve foot placement of the paretic limb. Foot placement was evaluated before, during, and after application of somatosensory electrical stimulation to the paretic foot during a targeted stepping task. Starting from standing, twelve chronic stroke participants initiated movement with the non-paretic limb and stepped to one of five target locations projected onto the floor with distances normalized to the paretic stride length. Targeting error and lower extremity kinematics were used to assess changes in foot placement and limb control due to somatosensory stimulation. Significant reductions in placement error in the medial–lateral direction (p = 0.008) were observed during the stimulation and post-stimulation blocks. Seven participants, presenting with a hip circumduction walking pattern, had reductions (p = 0.008) in the magnitude and duration of hip abduction during swing with somatosensory stimulation. Reductions in circumduction correlated with both functional and clinical measures, with larger improvements observed in participants with greater impairment. The results of this study suggest that somatosensory stimulation of the paretic foot applied during movement can improve the precision control of foot placement

GeneWaltz--A new method for reducing the false positives of gene finding

<p>Abstract</p> <p>Background</p> <p>Identifying protein-coding regions in genomic sequences is an essential step in genome analysis. It is well known that the proportion of false positives among genes predicted by current methods is high, especially when the exons are short. These false positives are problematic because they waste time and resources of experimental studies.</p> <p>Methods</p> <p>We developed GeneWaltz, a new filtering method that reduces the risk of false positives in gene finding. GeneWaltz utilizes a codon-to-codon substitution matrix that was constructed by comparing protein-coding regions from orthologous gene pairs between mouse and human genomes. Using this matrix, a scoring scheme was developed; it assigned higher scores to coding regions and lower scores to non-coding regions. The regions with high scores were considered candidate coding regions. One-dimensional Karlin-Altschul statistics was used to test the significance of the coding regions identified by GeneWaltz.</p> <p>Results</p> <p>The proportion of false positives among genes predicted by GENSCAN and Twinscan were high, especially when the exons were short. GeneWaltz significantly reduced the ratio of false positives to all positives predicted by GENSCAN and Twinscan, especially when the exons were short.</p> <p>Conclusions</p> <p>GeneWaltz will be helpful in experimental genomic studies. GeneWaltz binaries and the matrix are available online at <url>http://en.sourceforge.jp/projects/genewaltz/</url>.</p